Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier

Abstract

Therapeutic antibody drug development is a rapidly growing sector of the pharmaceutical industry. However, antibody drug development for the brain is a technical challenge, and therapeutic antibodies for the central nervous system account for ∼3% of all such agents. The principal obstacle to antibody drug development for brain or spinal cord is the lack of transport of large molecule biologics across the blood-brain barrier (BBB). Therapeutic antibodies can be made transportable through the blood-brain barrier by the re-engineering of the therapeutic antibody as a BBB-penetrating bispecific antibody (BSA). One arm of the BSA is the therapeutic antibody and the other arm of the BSA is a transporting antibody. The transporting antibody targets an exofacial epitope on a BBB receptor, and this enables receptor-mediated transcytosis (RMT) of the BSA across the BBB. Following BBB transport, the therapeutic antibody then engages the target receptor in brain. RMT systems at the BBB that are potential conduits to the brain include the insulin receptor (IR), the transferrin receptor (TfR), the insulin-like growth factor receptor (IGFR) and the leptin receptor. Therapeutic antibodies have been re-engineered as BSAs that target the insulin receptor, TfR, or IGFR RMT systems at the BBB for the treatment of Alzheimer’s disease and Parkinson’s disease.

Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport

“…The biologic TNFIs have not been developed as new treatments for PD, or other neurodegenerative conditions, because biologic TNFIs do not cross the BBB. Decoy receptors, such as etanercept, do not cross the BBB ( Boado et al, 2010b ), and therapeutic antibodies, such as adalimumab or infliximab, do not cross the BBB ( Pardridge, 2023a ). Successful development of the biologic TNFIs as drugs for the brain requires that these pharmaceuticals are re-engineered to enable transport across the BBB ( Pardridge and Boado, 2012 ).…”

“…In parallel with the development of anti-Abeta amyloid antibodies (AAA) for Alzheimer’s disease (AD), anti-SYN therapeutic antibodies have entered clinical trials for the treatment of PD. Since therapeutic antibodies do not cross the BBB ( Pardridge, 2023a ), the failure of the anti-SYN clinical trials in PD might be anticipated. Therapeutic antibodies for the CNS that have received FDA approval include antibodies for multiple sclerosis (MS), glioma, and AD.…”

“…The choice to engineer the BBB-directed arm of the BSA in a monovalent format insured low affinity of the BSA for the BBB IGF1R. As the affinity of the BSA for the BBB receptor is reduced, the therapeutic injection dose (ID) of the BSA must be proportionately increased ( Pardridge, 2023a ). The 6-hydroxydopamine or MPTP rodent models of experimental PD do not generate SYN aggregates that comprise the Lewy bodies of human PD ( Tieu, 2011 ; Paul and Sullivan, 2019 ).…”

“…Therapeutic antibodies do not cross the BBB ( Pardridge, 2023a ). Yet, several therapeutic antibodies directed against α-synuclein (SYN) entered clinical trials for PD.…”

The proteome of the blood–brain barrier in rat and mouse: highly specific identification of proteins on the luminal surface of brain microvessels by in vivo glycocapture

“…The tight regulation of molecules crossing the BBB represents one of the largest challenges in the treatment of neurological diseases, such as Alzheimer’s and Parkinson’s disease, since many therapeutics are not able to enter the brain parenchyma due to their inability to cross the BBB efficiently, including nearly all protein-based drugs such as antibodies. One promising approach to facilitate trafficking of protein therapeutics into the brain is to use a “carrier” protein that binds to a transcytosing receptor present on the surface of the endothelial cells, allowing the therapeutic to piggyback on this receptor to gain access into the brain through receptor-mediated transcytosis (RMT) [ 7 – 10 ]. A thorough profiling of the proteins present at the BBB would improve our understanding of this unique physiological structure and the proteins responsible for trafficking through the BBB.…”